Process for the preparation of triazolones

ABSTRACT

Described is a process for preparing triazolone compounds of the formula   &lt;IMAGE&gt;   comprising heating a mixture of a compound of the formula   &lt;IMAGE&gt;   and a hydrazine derivative of the formula R5-NH-NH-CHO, R5-NH-NH-C(O)OC(CH3)3 or R5-NH-NH-C(O)OCH2C6H5, optionally in the presence of an added base.

The present application is a continuation of U.S. application Ser. No.08/425,028 filed Apr. 19, 1995.

The present invention comprises a process for preparing triazolones andmore particularly for preparing trisubstituted tetrahydrofuran triazoleantifungals.

BACKGROUND OF THE INVENTION

PCT International Publication Nos. WO 89/04829 and WO 93/09114, and U.S.Pat. No. 5,039,676 disclose substituted tetrahydrofuran azole andimidazole compounds having utility as antifungal agents. Dioxolanylimidazole and triazole antifungal agents and related compounds aredescribed in U.S. Pat. Nos. 4,619,931, 4,861,879, 4,735,942 and4,791,111. A number of processes for the synthesis of these compoundsare known.

For example, PCT International Publication No. WO93/09114 discloses aprocess for the synthesis of trisubstituted tetrahydrofuran azoleantifungals by reacting a tosylate of the formula (I) ##STR3## wherein Xis both F or both Cl or one X is F and the other is Cl, with a compoundof the formula (II) ##STR4## wherein R" is alkyl, alkenyl, alkynylcycloalkyl, etc. The synthesis of a compound of the formula (I) isdescribed in PCT International Publication No. WO94/25452. WO93/09114also describes the conversion of a compound of the formula ##STR5##wherein W represents ##STR6## to a compound of the formula ##STR7##which is subsequently N-alkylated to give a compound of the formula##STR8## wherein R" is as defined above.

N-alkylation of the triazolone group as described in the prior art isinefficient, requiring a large excess of an expensive alkylating agent,typically an alkyl bromide, and results in a mixture of N-alkylated andO-alkylated triazolone products, necessitating laborious purificationmethods and giving low yields of the N-alkylated triazolone.

SUMMARY OF THE INVENTION

The present invention solves the aforementioned problems by providing anefficient process for preparing N-substituted triazolones. In apreferred embodiment, the instant process provides a method forpreparing N-alkylated triazolone intermediates which are useful in thesynthesis of tetrahydrofuran azole antifungal agents. The instantlyclaimed process is free of competing O-alkylation reactions, avoids theneed for a large excess of alkylating agent, and proceeds in good yieldproducing a product of high purity. The process of the present inventionutilizes inexpensive starting materials and can be used to prepare awide variety of N-alkyl triazolone intermediates.

The process of the present invention comprises heating a mixture of acompound of the formula ##STR9## wherein: B is aryl, substituted aryl ora group of the formula ##STR10## wherein R is C₆ H₅ CH₂, CH₃, H or agroup of the formula ##STR11## where G is imidazolyl or triazolyl, E isCH₂ or O, and each X is independently F or Cl; and

D is C₁ -C₆ alkyl, aryl, substituted aryl or aryl(C₁ -C₆ alkyl); with:

(a) a hydrazine derivative of the formula Z--NH--NH--R⁵, wherein R⁵ isC₁ -C₂₀ alkyl or substituted C₁ -C₂₀ alkyl, and Z is --CHO; or

(b) a hydrazine derivative of the formula Z--NH--NH--R⁵, wherein R⁵ isas defined above and Z is --C(O)OC(CH₃)₃ or --C(O)OCH₂ C₆ H₅, followedby hydrolyzing the Z group, and heating with a trialkylorthoformate andformic acid, to form a triazolone of the formula ##STR12## wherein B andR⁵ are as defined above. The process of the present invention isoptionally carried out in the presence of an added base.

In a preferred embodiment, the present invention provides a process forpreparing compounds of the formula (III) ##STR13## wherein: R is C₆ H₅CH₂, CH₃, H or W;

R ¹ and R² are independently C₁ -C₆ alkyl or Y-substituted C₁ -C₆ alkyl,wherein Y is --OH or --OR⁴, and wherein R⁴ is a hydroxyl protectinggroup;

or R¹ and R² together with the carbon atom to which they are attachedcomprise a C₄ -C₇ carbocyclic ring or a Y-substituted C₄ -C₇ carbocyclicring, wherein Y is as defined above; and

W represents ##STR14## wherein each X is independently Cl or F;comprising heating a compound of the formula (IV) ##STR15## wherein R isC₆ H₅ CH₂, H, CH₃ or W, and R³ is phenyl, with:

(a) a hydrazine derivative of the formula R¹ R² CH--NH--NH--Z, wherein Zis --CHO, and R¹ and R² are as defined above, provided that Y is --OR⁴ ;or

(b) a hydrazine derivative of the formula R¹ R² CH--NH--NH--Z, wherein Zis --C(O)OC(CH₃)₃ or --C(O)OCH₂ C₆ H₅, and R¹ and R² are as definedabove, provided that Y is --OR⁴, followed by hydrolyzing the Z group,and heating with a trialkylorthoformate and formic acid, to form acompound of the formula (III) ##STR16## wherein R, R¹ and R² are asdefined above provided that Y is --OR⁴. Compounds of the formula (III)wherein Y is --OH are prepared by deprotecting a compound of the formula(III) wherein Y is --OR⁴. Treating a compound of the formula (III),wherein R is C₆ H₅ CH₂ or CH₃, with HBr provides a compound of theformula (IIIa) ##STR17## wherein R¹ and R² are as defined above, i.e., acompound of the formula (III) wherein R is H.

The present invention further comprises a process for converting acompound (III), as defined above, having the structural formula (XVII)##STR18## wherein R is H and Y is --OR⁴, to a compound of the formula(XVII) wherein R is W, comprising reacting a compound of the formula(XVII), wherein R is H, with a compound of the formula ##STR19## whereinQ is a leaving group and X is as defined above, in the presence of abase, and optionally deprotecting to form a compound (XVII) wherein R isW and Y is --OH.

In a more preferred embodiment the present invention provides a processfor preparing compounds of the formula (III) as described above whereinthe hydrazine of formula R¹ R² CH--NH--NH--Z is prepared via a processcomprising the steps:

(a) reacting a ketone of the formula R¹ R² C(O), wherein R¹ and R² areas defined above provided that Y is --OR⁴, with a compound of theformula H₂ N--NH--Z, wherein Z is as defined above, to form a compoundof the formula R¹ R² C═N--NH--Z; and

(b) reducing the product of step (a) to form a compound of the formulaR¹ R² CH--NH--NH--Z.

DETAILED DESCRIPTION

All publications cited herein are incorporated in their entirety byreference.

As used herein, the term:

"alkyl" means a straight or branched alkyl chain having the number ofcarbon atoms specified; and "substituted alkyl" means an alkyl groupbearing one to three substituents selected from halo, C₁ -C₆ alkoxy,aryloxy;

"aryl" means a carbocyclic aromatic group, such as phenyl or naphthyl;and "substituted aryl" means an aryl group bearing one to threesubstituents selected from halo, alkyl, C₁ -C₆ alkoxy;

"halo" means a fluoro, chloro, bromo or iodo group;

"aryl(alkyl)" means an alkyl group substituted by an aryl group, benzylfor example;

"hydride reducing agent" means a metal hydride reagent, such as NaBH₄,Red-Al, DIBAL-H, L-Selectride, Vitride, LiBH₄, LiAlH₄, LiAl(OtBu)₃ H,NaCNBH₃, DMAB, zinc borohydride, calcium borohydride, a combination ofLiBH₄ and ZnBr₂, or a combination of NaBH₄ and LiCl;

"base" means a non-nucleophilic basic compound capable of facilitatingthe reaction between a compound of the formula (IV) and a hydrazine ofthe formula R¹ R² CH--NH--NH--Z, such as a tertiary amine base,hydroxide base, DBU, DBN, Dabco, a moderate base or phosphazene base;

"moderate base" means Na₂ CO₃, Li₂ CO₃ or K₂ CO₃ ;

"phosphazene base" means a base which is a cyclic or linear oligomer orpolymer comprising alternating nitrogen and phosphorous atoms, such as acyclic trimer or cyclic tetramer, having two substituents on eachphosphorous atom;

"tertiary amine base" means bases such as Et₃ N, DMAP or Hunigs base, aswell as analogous polymer supported bases comprising one or moretertiary amino groups;

"hydroxide base" means an alkali metal hydroxide, such as NaOH, KOH orLiOH, or Bu₄ NOH; and

"trialkylorthoformate" means an orthoester of the formula HC(O-alkyl)₃,wherein each O-alkyl group comprises from 1-6 carbon atoms, such asO--CH₃, OC₂ H₅ O--C₃ H₇ and O--C₄ H₉.

As used herein the following reagents and solvents are identified by theabbreviations indicated: methanol (MeOH); t-butyl methyl ether (TBME);triethylamine (Et₃ N); sodium bis(2-methoxyethoxy)aluminum hydride(Red-Al); di-isobutylaluminum hydride (DIBAL-H); lithiumtri(sec-butyl)borohydride (L-Selectride); Vitride; lithiumtri-t-butoxyaluminohydride (LiAl(OtBu)₃ H); t-butylamineborane (tBuNH₂.BH₃); dimethylamineborane (DMAB); di-isopropylethylamine (Hunigs base);1,2-dimethoxyethane (DME); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);ethanol (EtOH); 14-diazabicyclo[2.2.2]octane (Dabco); tetrabutylammoniumhydroxide (Bu₄ NOH); 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); pyridiniump-toluenesulfonate (PPTS); acetic acid (HOAc);N-t-butoxycarbonylhydrazine (BOC-hydrazine); dibenzoyl-D-tartaric acid(D-DBTA); dibenzoyl-L-tartaric acid (L-DBTA).

The "hydroxyl protecting group", R⁴, is a protecting group which blocksan --OH group thereby preventing reactions involving the --OH group fromoccurring during the process of the present invention. Hydroxylprotecting groups are well known in the art and methods for theformation and removal of hydroxyl protecting groups are also well knownsuch as those described in Greene, et aL, "Protective Groups in OrganicSynthesis", 2nd ed., John Wiley & Sons, 10-142 (New York 1991).Preferred hydroxyl protecting groups for use in the present inventionare ethers, such as benzyl ether.

The term "leaving group" means a substituent which is susceptible todisplacement by a suitable nucleophile, and includes groups such ashalo; C₁ -C₆ alkoxy; --OS(O)₂ R⁵ wherein R⁵ is C₁ -C₄ alkyl, CF₃, aryl,substituted aryl or aryl(C₁ -C₄ alkyl); or --OC(O)R⁶ wherein R⁶ is C₁-C₆ alkyl, C₁ -C₆ alkoxy, aryl or substituted aryl. The particularleaving group to be used is in part dependent upon the strength of thenucleophile, with more labile groups, such as halo and in particular--OS(O)₂ R⁵, being used in conjunction with weaker nucleophiles. Theleaving group Q is preferably a group of the formula --OS(O)₂ R⁵,wherein R⁵ is as defined above, and is more preferably such a groupwherein R⁵ is selected from --CH₃, --CF₃, --C₆ H₅, --C₆ H₄ CH₃, --C₆ H₄Br and --C₆ H₄ Cl. The leaving group L is preferably: C₁ -C₆ alkoxy,halo or --OC(O)R⁶, wherein R⁶ is as defined above.

The present invention comprises a process for preparing a triazolone ofthe formula (X) as shown in Reaction Scheme 1. ##STR20##

In Reaction Scheme 1, compound (XI) is heated at 50° to 90° C. with ahydrazine of the formula R⁵ --NH--NH--Z, wherein B, D, R⁵ and Z are asdefined above, optionally in the presence of a base, such as Et₃ N, DBU,K₂ CO₃ or a phosphazene base, in a suitable solvent, such as toluene, toform an intermediate of the formula (XII). Upon further heating at 80°to 150° C., the intermediate (XII) is converted to a compound of theformula (X).

In a preferred embodiment the present invention comprises a process forpreparing a compound of the formula (III) as shown in Reaction Scheme 2.##STR21##

In Reaction Scheme 2, compound (IV), wherein R and R³ are as definedabove, is heated at 50° to 90° C. with a hydrazine of the formula R¹ R²CH--NH--NH--Z, wherein R¹, R² and Z are as defined above, provided thatY is --OR⁴, in the presence of a base, such as Et₃ N, DBU, K₂ CO₃ or aphosphazene base, in a suitable solvent, such as toluene, to form anintermediate of the formula (V). The intermediate (V) is not isolatedand upon further heating at 80° to 150° C., the intermediate (V) isconverted to a compound of the formula (III) wherein R, R¹ and R² are asdefined above, provided that Y is --OR⁴.

The compound (III), wherein Y is --OR⁴, is optionally deprotected toform a compound of the formula (III) wherein Y is --OH. For example,where R⁴ is benzyl, the deprotection can be accomplished by treatingwith an aqueous solution comprising 40% to 50% HBr, preferably about 48%HBr, at a temperature of -10° to 40° C., preferably about 15° to 30° C.A preferred method of deprotection when R⁴ is benzyl comprises treatingwith a palladium catalyst, such as 5% Pd/C, in the presence of formicacid.

A compound of the formula (III), wherein R is C₆ H₅ CH₂ or CH₃, isoptionally treated with HBr to form a compound of the formula (IIIa).

In a more preferred embodiment, the present invention provides a processas described in Reaction Scheme 2 wherein the hydrazine of formula R¹ R²CH--NH--NH--Z (IX) is prepared by a process as shown in Reaction Scheme3. ##STR22##

In Step A of Reaction Scheme 3, a ketone of the formula (VI), wherein R¹and R² are as defined above provided that Y is --OR⁴, is reacted with ahydrazine of the formula (VII), wherein Z is as defined above, at atemperature of 0° to 80° C., preferably at 20° to 60° C., and mostpreferably at about 30° to 50° C., to form a compound of the formula(VIII).

In Step B, the compound (VIII) from step A is reduced by treating with ahydride reducing agent, preferably NaBH₄, in a suitable solvent, such asan C₁ -C₄ alcohol, preferably MeOH, EtOH or i-PrOH, to form thehydrazine (IX).

Compounds of the formula (III) wherein R¹ or R² is Y-substituted alkylmay contain one or more chiral centers. For such compounds, allstereoisomers, including individual stereoisomers, and mixtures orracemates thereof, are within the scope of the present invention. Suchcompounds are readily prepared using a starting ketone (VI) having theappropriate stereochemistry.

Compounds of the formula (IV), (VI) and (VII) are known or can bereadily prepared via established methods.

Compounds of the formula (XI) ##STR23## wherein B is a group of theformula ##STR24## R Is a group of the formula ##STR25## and D, E, X andG are as deemed above, can be prepared by the process described inReaction Scheme 4. ##STR26##

In Step A of Reaction Scheme 4, a compound of the formula (XIII),wherein Q is a leaving group, is reacted with the amino alcohol (X1V) inthe presence of a base to form a compound of the formula (XV), wherein Ris as defined above. The reaction occurs regioselectively via selectivereaction of the phenolic hydroxyl group of compound (XIV), and does notrequire protection of the amino terminus of the molecule.

In Step B, the product (XV) of Step A is treated with a compound of theformula (XVI), wherein L is a leaving group and D is as defined above,to form a compound of the formula (XI) as defined above.

The present invention also comprises a process for regioselectivelyreacting compound (XW) with a compound of the formula (XIII) to form acompound of the formula (XV), as described in Step A of Reaction Scheme4.

The following preparations and examples are illustrative of the processof the present invention. ##STR27##

The chiral benzyloxyamide is prepared from ethyl (S)-lactate viasubstantially the same procedure as described in Kobayashi, et al.,Bull. Chem Soc. Jpn., 62, 3038-3040 (1989). ##STR28##

The product of Step A is converted to the corresponding benzyl ether viaprocedures such as the one described in Kobayashi, et al., supra.Alternatively, benzylation can be carried out via other methods known inthe art such as those described in Greene, et al., "Protective Groups inOrganic Synthesis", 2nd edition, p. 47-49, John Wiley & Sons, New York,(1991). ##STR29##

Combine 16 L of anhydrous THF and 12.5 kg of the 2-(S)-benzyloxyamidefrom Step A under nitrogen atmosphere and stir while cooling to -10° to-5° C. Slowly (over a period of 60 to 90 min.) add 58.4 kg of ethylmagnesium bromide as a 1M solution in THF such that the temperatureremains at -10° to -3° C. Stir the reaction mixture at -4° to -2° C for3 to 5 hours. Slowly add the reaction mixture to a stirred mixture of125 L of TBME and 7 L of acetic acid at -10° to -5° C. such that thetemperature remains at 0° to 15° C. Stir the mixture for another 20 to30 min., then add a combination of 12.5 L of TBME, 1.25 L of HOAc and 50mL of water. Agitate the mixture, then allow it to settle and separatethe organic and aqueous layers. Wash the organic layer successively with50 L of water, 50 L of 5% NaHCO₃ (aqueous), and 50 L of water.Concentrate the organic layer to a volume of 25 L via distillation at55° to 60° C., add 25 L of TBME and cool to <30° C. Concentrate again toa volume of 25 L then concentrate in vacuo (at a temperature of about50° C.) to give the ketone product as a residue.

Dissolve the product in 15 L of DME to give a solution of the productfor use in Step D. ##STR30##

Combine 103 L of DME and 12 kg of ZnBr₂ and heat the mixture to 60° to65° C. to dissolve the solids. Cool the mixture to 25° to 30° C. Slowlyadd this solution to a mixture of 1.24 kg of LiBH₄ and 21 L of DME at 0°to 10° C. such that the temperature remains at 0° to 15° C. Cool theresulting mixture to -5° to 5° C. and stir for 40 to 50 min. Slowly addthe product solution from Step C such that the temperature remains at-5° to 5° C. Stir the mixture until the reaction is complete by HPLC.[HPLC analysis procedure: Dilute a 0.5 mL aliquot of the reactionmixture to a volume of 250 mL with the mobile phase MeOH/water/H₃ PO₄(50:50:0.1) and analyze 5 μL of that solution using a Zorbax® RX-ODScolumn and a U.V. detector.] Slowly add 15 L of acetone such that thetemperature remains at 0° to 20° C. Slowly add the resulting mixture toa stirred mixture of 21 L of water and 21 kg of ice such that thetemperature remains at 5° to 15° C. Slowly add a mixture of 10 L ofconc. HCl, 83 L of water and 21 kg of ice, keeping the temperature at 5°to 15° C., then stir for 20 min. Add 103 L of TBME and stir for 20 min.Allow the mixture to settle and separate the aqueous and organic layers.Extract the aqueous layer with 44 L of TBME and combine the organiclayers. Wash with water (4×41 L), then concentrate the organic solutionvia distillation at a temperature of <55° C to a volume of 12.5 L. Add21 L of TBME and again concentrate to a volume of 12.5 L. Concentrate invacuo at a temperature of <50° C. to give the 2-(S)-3(R,S)-alcoholproduct as a residue. ##STR31##

Combine 6.3 kg of the 2(S)-3(R,S)-alcohol product of Step D and 18.9 Lof CH₂ Cl₂ and stir while cooling to 0° to 5° C. Add 7.6 kg ofp-chlorobenzenesulphonyl chloride. Slowly add a solution of 5.2 kg ofDMAP in 18.9 L of CH₂ Cl₂ while keeping the reaction temperature at <10°C. Stir the mixture at 15° to 25° C. until the reaction is complete byHPLC (about 16 hours). [HPLC analysis procedure: Extract a 1 mL aliquotof the mixture with dilute HCl (aqueous), then dilute to a volume of 250mL with MeOH and analyze a 5 μL sample of that solution using a Zorbax®RxC8 column, and MeOH/water (75:25) as the mobile phase.] Add 6.3L of25% NaOH (aqueous) and 6.3 L of water to the mixture and stir at 15° to25° C. for about 1 hour. Slowly add the resulting mixture to a mixtureof 25.2 L of water, 31.5 kg of ice, and 2.5 L of H₂ SO₄. Separate thelayers and wash the organic layer successively with 63 L of 5% NaHCO₃(aqueous), and water (2×12.6 L). Concentrate the organic layer first bydistillation at 60° C., then in vacuo at <60° C. to give thechlorobenzenesulfonate of the 2-(S)-3(R,S)-alcohol as a residue.##STR32##

Combine 11.0 kg of the product of Step E and 16.5 L of EtOH, then add11.0 L of hydrazine monohydrate and stir the mixture at 65° C. until thereaction is complete (about 16 hours). Cool to 15° to 25° C., add 11.0 Lof water and 55.0 L of TBME, then stir for 15 min. Allow the mixture tosettle, separate the layers and extract the aqueous layer with 55 L ofTBME. Combine the organic layers and wash with water (2×11.0 L). Slowlyadd the organic solution to a solution of 11.0 kg of L-DBTA in 110.0 Lof TBME and stir at 15° to 25 ° C. for 2 hours. Filter to collect theresulting precipitate and wash the solid with 22.0 L of TBME. Dry thesolid in a vacuum oven at 25° C.±5° C. to give the 2(S)-3(S)-chiralhydrazine product as its L-DBTA salt. ##STR33##

Combine 10 kg of the product of Step F, (alternatively, the product ofPreparation 2 can be used), and 100 L of ethyl formate and heat themixture at reflux for I to 2 hours until all of the solid is dissolvedand the reaction is complete by HPLC. [HPLC analysis procedure: Combine2 drops of the reaction mixture and 3 mL of 1% Et₃ N in MeOH and analyzeusing a Zorbax® Rx-C8 column, and MeOH/water (75:25) as the mobilephase.]Add 60.0 L of TBME, then add the resulting mixture to a mixtureof 2.8 kg of Na₂ CO₃ and 50 L of water and stir the mixture for 15 min.Allow the layers to settle, separate the layers, then wash the organiclayer successively with a solution of 0.5 kg NaHCO₃ in 10 L of water,and a solution of 0.5 kg of NaCl in 10 L of water. Concentrate theorganic solution in vacuo at a temperature of <40° C., add 60.0 L of CH₂Cl₂ and distill at atmospheric pressure at about 44° C. to give thetitle compound as a residue. ##STR34##

The 2(S)-3(R,S)-chlorobenzenesulfonate from Step E of Preparation I isconverted to a mixture of the 2(S)-3(R)-and 2(S)-3(S)-hydrazines astheir D-DBTA salts using D-DBTA and substantially the same procedure asdescribed in Step F of Preparation 1. Using L-DBTA as described inPreparation 1, the ratio of SS:SR isomers is 91:9, while a ratio of 96:4is obtained using D-DBTA. Recrystallization of the D-DBTA salt from asuitable solvent, such as iPrOH or a mixture of TBME and EtOH, providesthe 2(S)-3(S)-hydrazine having a ratio of SS:SR of >99: 1. This D-DBTAhydrazine can be used in Step G of Preparation 1. ##STR35##

Combine 65 g (0.328 moles) of the ketone product from Step C ofPreparation 1,180 mL of toluene and catalytic amount (500 mg, 2 mmoles)of PPTS, then slowly add (over a period of 15 min.) a solution of 49.15g (0.37 moles) of t-BOC-hydrazine in 200 mL of toluene at 20°-25° C.Stir the mixture at 2-°-25° C. for about 4 hours, then filter to isolatethe resulting solid. Wash the solid with cold heptane (3 X 50 mL) anddry at 50° C. in vacuo to give 80.5 g (80% yield) of the t-BOC-hydrazoneproduct. m.p.=115.5° C. ##STR36##

Dissolve 12 g (40 mmol) of the t-BOC-hydrazone product of Step A in 150mL of CH₂ C₁₂ and cool the mixture to -85° C. Slowly add (over a periodof 90 min.) 156 mL of a 1M solution of DIBAL-H in a CH₂ Cl₂ and stir at-80° to -85° C. for 5 hours. Warm the mixture to 0°-5° C. and add 250 mLof water. Separate the phases and wash the organic phase with water(3×50 mL). Concentrate/n vacuo to give 10.6 g (86% yield) of a mixtureof 94% (S,S)- and 6% (S,R)-BOC-hydrazines.

Using the hydride reducing agent, solvent and reaction conditionsindicated, and following substantially the same procedure, the followingresults were obtained:

    __________________________________________________________________________    Hydride Reducing                                                                            Reaction                                                                            Reaction Time                                                                         % (S,S)                                                                            %                                            Agent    Solvent                                                                            Temp. (hours) isomer*                                                                            Yield                                        __________________________________________________________________________    NaBH.sub.4                                                                             EtOH 0°-5° C.                                                              24      30.9%                                                                              --                                           NaBH.sub.4                                                                             ETOH/                                                                              0°-5° C.                                                              18       --  --                                                    AcOH                                                                 NaCNBH.sub.3                                                                           EtOH 0°-5° C.                                                              70      21%  --                                           LiBH.sub.4                                                                             DME  0°-5° C.                                                              5 days  41%  86%                                          LiBH.sub.4 +                                                                           DME  0°-5° C.                                                              24      21   --                                           ZnBr.sub.2                                                                    t-BuNH.sub.2.BH.sub.3                                                                  CH.sub.2 Cl.sub.2                                                                  0°-5° C.                                                              --       --  **                                           + TiCl.sub.4                                                                  t-BuNH.sub.2.BH.sub.3                                                                  CH.sub.2 Cl.sub.2                                                                  -75° C.                                                                      3        --  **                                           + SnCl.sub.4                                                                  t-BuNH.sub.2.BH.sub.3                                                                  CH.sub.2 Cl.sub.2                                                                  -75° C.                                                                      --      29.4%                                                                              45%                                          + AlCl.sub.3                                                                  t-BuNH.sub.2.BH.sub.3                                                                  CH.sub.2 Cl.sub.2                                                                  0°-5° C.                                                              36       5%  --                                           Bu.sub.4 NBH.sub.4                                                                     CH.sub.2 Cl.sub.2                                                                  0°-5° C.                                                              26       --  --                                           Bu.sub.4 NBH.sub.4 +                                                                   CH.sub.2 Cl.sub.2                                                                  0°-5° C.                                                              --       --  **                                           TiCl.sub.4                                                                    DMAB     CH.sub.2 Cl.sub.2                                                                  0°-5° C.                                                              17       --  --                                           LiAlH.sub.4                                                                            THF  0°-5° C.                                                              20      19.2%                                                                              67%                                          L-Selectride                                                                           THF  -60° C.                                                                      16       --  --                                           DIBAL-H  CH.sub.2 Cl.sub.2                                                                  -70° C.                                                                      4       92.1%                                                                              76%                                          Vitride  toluene                                                                            0°-5° C.                                                              19      37.5%                                                                              84%                                          DIBAL-H  CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      6       91%  69%                                          Vitride  CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      23      70%  --                                           DIBAL-H  CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      23      81.5%                                                                              27%                                          DIBAL-H  THF  -80° C.                                                                      2.5      --  --                                           Vitride  CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      47      30.7%                                                                              45%                                          DIBAL-H  CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      5       93.6%                                                                              86%                                          DIBAL-H  toluene                                                                            -95° C.                                                                      29       0%  94%                                          DIBAL-H  toluene/                                                                           -110° C.                                                                     18       0%  96%                                                   CH.sub.2 Cl.sub.2                                                    DIBAL-H  CH.sub.2 Cl.sub.2                                                                  0°-5° C.                                                              0.5     71.4%                                                                              68%                                          DIBAL-H  CH.sub.2 Cl.sub.2 /                                                                -100° C.                                                                     21      65%  56%                                                   toluene                                                                       (9:1)                                                                LiAl(OtBu).sub.3 H                                                                     CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      0.5      0%  --                                           DIBAL-H  CH.sub.2 Cl.sub.2 /                                                                -100° C.                                                                     72      65%  --                                                    CH.sub.3 CCl.sub.3                                                   DIBAL-H  CH.sub.2 Cl.sub.2 /                                                                -95° C.                                                                      6       90%  81%                                                   CH.sub.3 CCl.sub.3                                                   DIBAL-H  CH.sub.2 Cl.sub.2                                                                  -85° C.                                                                      5       93%  70%                                          __________________________________________________________________________     *The percentage of (S,S)BOC-hydrazine is determined by HPLC. The              (S,R)isomer comprises the remainder of the product isolated, (i.e., 0%        (S,S) means that 100% (S,R) was formed).                                      **Decomposition occurred.                                                

EXAMPLE 1 ##STR37##

Combine 220 g (3.66 mole) of formylhydrazine and 947 g (10.99 mole) of3-pentanone and heat the mixture at 40° C. for about 2 hours, at whichtime all of the hydrazine has reacted (as determined by 1H NMR). Distillat 50° C., 150 mbar, to remove the excess 3-pentanone (520 mL) leaving aresidue. Add 2.7 L of n-heptane to the residue and heat the mixture to80° C. Filter the hot mixture and concentrate the filtrate bydistillation at 91°-93° C. to remove a total of 1200 mL of n-heptane.Cool the remaining mixture to 0° to 5° C. and allow the product tocrystallize. Collect the solid product by filtration, wash the solidwith n-heptane and dry the solid at 40° C. in vacuo to give 408.6 g (87%yield) of the formylhydrazone product. ##STR38##

Slowly add a solution of 64.1 g (0.5 mole) of the Product of Step A in640 mL of i-PrOH to a mixture of 20.8 g (0.55 mole) of NaBH₄ in 225 mLof 1:1 i-PrOH/water at 10°-15° C., over a period of 50 min. Stir theresulting mixture at 10°-15° C. for about 90 min., then add 125 mL ofacetone and stir for 1 hour at 10°-20° C. Distill at 50° C., 200 mbar,to remove the solvent and treat the resulting residue with 300 mL ofwater and 200 mL of TBME. Separate the phases and extract the aqueousphase with 50 mL of TBME. Combine the organic phase and extract and washsuccessively with 100 mL of water and 2×50 mL of brine, then dry overNa₂ SO₄. Distill off the solvent at 50° C., 150 mbar, then add tolueneand azeotropically distill residual water to give 57 g (87.7% yield) ofa residue. Distill the residue (50° C.)to give a 55% yield of the formylhydrazine product. m.p.=35°-37° C. ##STR39##

Combine 1.43 g (11 mmol) of the Product of Step B, 4.03 g (10 mmol) ofthe methoxy carbamate, 15.3 mg (0.1 mmol) of DBU and 50 mL of tolueneand heat to 80° C. for about 7.5 hours to give a mixture containing theuncyclized intermediate, which can be isolated if desired. Heat themixture at reflux for about 8 hours to complete the formation of thetriazolone. Distill off the toluene to give a residue and treat theresidue with 15 mL of MeOH. Cool the mixture to 0°-5° C. and stir for 1hour. Filter to collect the solid product, wash the solid with 2×10 mLof MeOH, then dry the solid at 50° C. in vacuo to give the desiredtriazolone product (84% yield).

EXAMPLE 2 ##STR40##

Combine 132 g (1.0 mole) of BOC-hydrazine, 0.2 g (0.8 mmol) of PPTS and400 mL of n-hexane and heat the mixture to 40° C. Add 107.6 g (1.25mole) of 3-pentanone and heat the mixture to 60° C. for 15 min., thenstir at 50° C. for 1-2 hours. Cool the mixture to 15° C. and filter tocollect the solid product. Wash the solid with 150 mL of n-hexane anddry the solid at 50° C. in a draft oven to give 184 g (91% yield) of theBOC-hydrazone product. m.p.=109°-110° C. ##STR41##

Combine 125 g (0.625 mole) of the hydrazone product of Step A, 875 mL ofMeOH and 375 mL of water and add a few drops of 30% NaOH (aqueous) toadjust to pH=11. Add 47.5 g (1.26 mole) of NaBH₄ to the mixture at20°-25° C. and stir for 16 hours. Add a few drops of concentrated HCl toreadjust to pH=11.5, then add 15.0 g (0.397 mole) of NaBH₄ and stir for15 hours at 20°-25° C. Add conc. HCl to readjust to pH=11.5, then add 10g (0.26 mole) of NaBH₄ and stir for 2 hours at 20°-25° C. Add 500 mL ofTBME, filter to remove the resulting precipitate and wash the solid with500 mL of TBME. Add 500 mL of water to the filtrate and separate thephases. Extract the aqueous phase with 2×500 mL of TBME. Combine theorganic phases and wash with 500 mL of water, then with 500 mL of brine.Distill off the solvent from the organic phase at 50° C., 200 mbar, togive a residue. Treat the residue with 300 mL of TBME, filter andconcentrate the filtrate in vacuo to give a 93% field of theBOC-hydrazine derivative product. ##STR42##

Combine 12.6 g (62.4 mmol) of the BOC-hydrazine derivative of Step B,20.1 g (49.8 mmol) of the carbamate, 5.5 g (54.35 mmol) of Et₃ N and 400mL of DME and heat the mixture to reflux (about 85° C.) for about 16hours. Filter the mixture and cool the filtrate to 0°-5° C. and stir at0°-5° C. for 1 hour. Collect the resulting solid by filtration, wash thesolid with 80 mL of DME and dry the solid at 50° C. in a draft oven togive an 82% yield of the uncyclized product. ##STR43##

Combine 10.2 g (19.96 mmol) of the product of Step C, 100 mL of DME and36 mL of concentrated HCl and heat the mixture at 48°-52° C. for about70 min. Cool the mixture to 20° C. and 22 mL of 30% NaOH (aqueous) toadjust to pH=12.5. Cool the mixture to 10° C. and stir for 1 hour.Filter and wash the solids with 30 mL of water, then dry the solids invacuo to give an 88% yield of the product. ##STR44##

Combine 4 g (9.73 mmol) of the product of Step D and 36 mL (328.7 mmol)of trimethyl orthoformate and heat the mixture to 75° C. Add 3 g (65mmol) of formic acid, then heat to 100° C. for 30 min. Cool the mixtureto 10° C. and stir for 1 hour. Filter to collect the solids, wash thesolids with 10 mL of CH₃ CN and n-hexane, then dry the solids in vacuoto give 3.4 g (82% yield) of the triazolone product.

EXAMPLE 3 ##STR45##

Formylhydrazine and 2-benzyloxy-3-pentanone are reacted usingsubstantially the same conditions as described in Example 1, Step A, toform the formylhydrazone product. ##STR46##

The formylhydrazone of Step B is reduced using NaBH₄ followingsubstantially the same procedure as described in Example 1, Step B, toform the formylhydrazine derivative product. ##STR47##

The N-(benzyloxyalkyl)triazolone product is prepared from the product ofStep B and the carbamate, using Et₃ N as the base and DME as solvent,via substantially the same procedure as described in Example 1, Step C.

EXAMPLE 4 ##STR48##

Add 50 g of the amino alcohol (4A-2) to a stirred solution of 750 mLDMSO at room temperature and 12 g NaOH dissolved in 84 mL H₂ O. Stir theresulting mixture for 5 min and then add 100 g of the chiralchlorobenzenesulfonate (4A-1). Stir overnight at room temperature andthen dilute with 3 L of water. Cool to about 5° C., stir for 0.5 hr andfilter. Wash the solid thus obtained with hexane to give 97.5 g of theproduct (4A). MS: FAB, 547 (M+H) ##STR49##

Slowly add 21.5 mL of PhOCOCI to a stirred solution of 85 g of theproduct (4A) of Step A, wherein W is as defined for Step A, in 650 mL ofCH₂ Cl₂ at room temperature. Stir at room temperature until the reactionis complete (2 to 8 hr). Cool the mixture to 0° C., wash with saturatedNaHCO₃ (aqueous) such that the pH of the aqueous layer remains basic.Separate the layers and extract the aqueous layer with CH₂ Cl₂. Combinethe CH₂ Cl₂ layers, then add 1.5 L of H₂ O and 2.5 L of hexane. Cool to0° C. and filter to collect the resulting solid. Wash the solidsequentially with water, 50% MeOH/H₂ O, and then hexane. Dry the solidto give 100.5 g of the product (4B), wherein W is as defined above. MS:FAB, 667 (M+H) ##STR50##

Combine 347 g of the product (4B) of step B, 137 g of the chiralhydrazine of Preparation 1, 85 g of type 4Å molecular sieves, 0.8 g ofDBU and 1400 mL of toluene, and heat the mixture at 75° to 85° C. for12-24 hrs to form the intermediate (4C-1). Raise the temperature to 100°to 110° C. and continue heating for 24 to 48 hrs. Cool the mixture to70° C. and filter through Celite®, washing with 700 mL of hot toluene.Distill the filtrate under vacuum to a volume of 1000 mL, then cool to40° C. and add 2400 mL of CH₂ Cl₂. Wash the resulting solutionsequentially with 0.5M aqueous NaOH (2×800 mL), 200 mL of water, 235 mLof 1M HCl (aqueous), 200 mL of water, and 250 mL of 5% NaHCO₃ (aqueous).Add 34 g of Darco® the solution, stir for 10 to 15 min, then filterthrough Celite®, washing with 400 mL of CH₂ Cl₂. Distill the filtrate atatmospheric pressure to a volume of 1000 mL, then distill in vacuo(temperature <70° C.) to give the product (4C). ##STR51##

Cool the product (4C) from Step C to 50° C., add 350 mL of HCO₂ H,continue cooling to 20° C., and add another 350 mL of HCO₂ H (350 mL).Add the resulting formic acid solution to a slurry of 85 g of 5% Pd/C(50% water wet) in 350 mL of HCO₂ H. Rinse with an additional 350 mL ofHCO₂ H to ensure complete transfer of material. Stir the mixture at 20 °C. overnight, then at 40° C. for 24 hrs. Filter the resulting mixturethrough Celite®, washing with 350 mL of HCO₂ H, and then with 700 mL ofMeOH. Concentrate the filtrate/n vacuo to a residue. Add 3500 mL of MeOHand 694 mL of NH₄ OH (aqueous) to the residue and heat the mixture atreflux for 1 to 2 hrs. Cool the mixture to 15° to 25° C. and filter tocollect the resulting solid. Wash the solid with 1400 mL of 1:1MeOH/water, then air dry the solid in a draft oven at 40° C. to give300.5 g of the title compound (1).

EXAMPLE 5 ##STR52##

Combine 12.6 g (15.9 mmol) of the product (4C) of Example 4, Step C, and300 mL of 48% HBr (aqueous). Stir the resulting mixture at roomtemperature for 24 hrs., then cool to 0° C. and add 4 N NaOH (aqueous)to adjust the pH of the mixture to 7.5-8. Stir for 30 min. at 0° C. thenfalter to collect the resulting solid. Wash the solid with 300 mL ofwater, then partition the solid between 100 mL of CH₂ Cl₂ and 100 mL ofbrine. Separate the layers and extract the aqueous layer with CH₂ Cl₂(3×50 mL). Combine the organic layers and wash with 50 mL of water, thendry over anhydrous MgSO₄. Concentrate in vacuo to a solid residue andrecrystallize from about 60 mL of 9:1 water/acetone. Dry therecrystallized solid in a vacuum oven for 18 hrs. at 45° C. to give 6.94g of the title compound (1). A second crop of 1.23 g of the titlecompound (1) is obtained from the mother liquor of therecrystallization. These materials were combined and slurried in hotTBME/hexane (1:2), cooled to 0° C., then filtered to give 8.2 g of thetitle compound (1). MS m/z=701.4 (M+1)

EXAMPLE 6 ##STR53##

Combine 12.0 g of the amino alcohol (4A-2), 110 mL of DMF, and 3.6 mLpyridine at room temperature, then slowly add 5.76 mL of C₆ H₅ OC(O)Cl.Stir the reaction mixture until the reaction is complete (4 to 18 hrs.),then dilute with water, cool to 0° to 5° C., and filter to obtain 17.4 gof the hydroxy carbamate product as a solid. MS: FAB, 390 (M+H).##STR54##

The product of Step A is converted to the chiral N-alkyl triazolone byheating with the chiral hydrazine of Preparation 1 under substantiallythe same conditions as described for Step C of Example 4.

EXAMPLE 7 ##STR55##

Combine 347 g Of the product (4B) of Example 4, Step B, 137 g of theproduct of Preparation 1, 0.8 g of DBU, 1100 mL of toluene and 85 g ofmolecular sieves and heat the mixture at 75° to 80° C. for three days.Cool to 70° C. and filter the hot mixture through Celite®, washing thefilter cake with 700 mL of hot toluene. Combine the filtrate and washingand concentrate/n vacuo at <50° C. to a volume of 1000 mL. Cool to 40°C., add 2400 mL of CH₂ Cl₂, then cool to 20° C. Wash (2×800 mL) with asolution prepared from 190 mL of 25% NaOH (aqueous) and 1400 mL ofwater, then wash successively with 200 mL of water, a solution of 35 mLconcentrated HCl and 200 mL of water, and 250 mL of 5% NaHCO₃ (aqueous).Add 34 g of Darco® then filter through Celite®, washing the filter cakewith 400 mL of CH₂ Cl₂. Distill at about 50° C. to remove the CH₂ Cl₂,then under vacuum at 68° C. to remove toluene, giving a residue. Coolthe residue to 50° C. and add 350 mL of formic acid. Cool to 20° C. andadd another 350 mL of formic acid to give a solution of the product tobe used directly in Step B. ##STR56##

Slowly add the product solution of Step A to a mixture of 85 g of 5%Pd/C and 350 mL of formic acid at 20° C. Stir the resulting mixture at21 ° C. for about 15 hours, then heat to 35° to 40° C. and stir for 24hours more. Cool the mixture to 20° C. and filter through Celite®,washing the filter cake with 390 mL of formic acid, then with two 350 mLportions of MeOH. Combine the filtrate and washings and concentrate invacuo at <70° C. to a residue. Add 1750 mL of MeOH to the residue andredistill under vacuum to a residue. Add 1000 mL of MeOH to the residueand stir overnight at room temperature. Dilute the solution with another2470 mL of MeOH, cool to 20° C. then add 694 mL of 28% NaOH (aqueous).Heat the mixture at reflux for 24 hours then cool slowly to 41 ° C. toform a precipitate. Maintain the temperature at 40° to 45° C. for 30min., then cool to 15° to 25° C. and stir for 2 hours. Filter to collectthe precipitate and wash the precipitate with 1400 mL of 1:1 MeOH/water.Dry the solid in a draft oven at 40° C. to give 300.5 g of the titlecompound (1).

EXAMPLE 8 ##STR57##

The product of Example 6 is reacted with the chiralchlorobenzenesulfonate (4A-1) of Example 4 under substantially the sameconditions as described in Example 4, Step A, to give the desiredcompound.

EXAMPLE 9 ##STR58##

Combine 2.16 g (8.0 mmol) of the aminophenol, 32 mL of DMSO and 0.95 g(8.5 mmol) of tBuOK at 0° C. Stir the resulting mixture at roomtemperature for 30 min., then add 1.04 g (8.2 mmol) of benzyl chlorideand stir at room temperature for 24 hours. Dilute the mixture with 150mL of water and filter to collect the resulting solid. Wash the solidwith 50 mL of 10% MeOH in water, then dry in vacuo (40 torr) at 60° C.to give 2.8 g (100% yield) of the product. ##STR59##

Combine 1.80 g (5.0 mmol) of the product of Step A, 30 mL of CH₂ Cl₂,0.55 g (7.0 mmol) of pyridine and 0.94 g (6.0 mmol) of phenylchloroformate at room temperature and stir for 3 hours. Add o.55 g orpyridine and 0.5 g of phenyl chloroformate and stir for 1 hour. Dilutewith 20 mL of water and stir for 1 hour. Filter to collect the resultingsolid to give 2.0 g (83% yield) of the product. MS (M+1)=480.5.##STR60##

The product of Step B is reacted with the chiral hydrazine ofPreparation 1 via substantially the same procedure as described forExample 4, Step C to give the chiral triazolone product. ##STR61##

Combine 50 mg (0.86 mmol) of the Product of Step C and 3 mL of 48% HBr(aqueous) at room temperature. Stir the mixture for 24 hours, thenconcentrate/n vacuo to give 60 mg of the title compound as its HBr salt.MS: (M) =409.4; (M+1)=410.4; (M+2)=411.4.

We claim:
 1. A process for preparing a triazolone compound of theformula ##STR62## wherein: B is aryl, substituted aryl or a group of theformula ##STR63## wherein R is C₆ H₅ CH₂, CH₃, H or a group of theformula ##STR64## where G is imidazolyl or triazolyl, E is CH₂ or O, andeach X is independently F or Cl; andR⁵ is C₁ -C₂₀ alkyl or substitutedC₁ -C₂₀ alkyl; comprising heating a mixture of a compound of the formula##STR65## wherein: B is as defined above, and D is C₁ -C₆ alkyl, aryl,substituted aryl or aryl(C₁ -C₆ alkyl); with:(a) a hydrazine derivativeof the formula Z--NH--NH--R⁵, wherein R⁵ is C₁ -C₂₀ alkyl or substitutedC₁ -C₂₀ alkyl, and Z is --CHO; or (b) a hydrazine derivative of theformula Z--NH--NH--R⁵, wherein R⁵ is as defined above and Z is--C(O)OC(CH₃)₃ or --C(O)OCH₂ C₆ H₅, followed by hydrolyzing the Z group,and heating with a trialkylorthoformate and formic acid, in the optionalpresence of base, to form a triazolone;wherein "substituted alkyl" meansan alkyl group bearing one to three substituents selected from the groupconsisting of halo, C₁ -C₆ alkoxy, and aryloxy; "aryl" means acarbocyclic aromatic group; and "substituted aryl" means an aryl groupbearing one to three substituents selected from the group consisting ofhalo, alkyl, and C₁ -C₆ alkoxy.
 2. The process of claim 1 wherein a baseis present in the mixture.
 3. A process for preparing a triazolonecompound of the formula ##STR66## wherein: R is C₆ H₅ CH₂, CH₃, H orW;R¹ and R² are independently C₁ -C₆ alkyl or Y-substituted C₁ -C₆alkyl, wherein Y is --OH or --OR⁴, and wherein R⁴ is a hydroxylprotecting group; or R¹ and R² together with the carbon atom to whichthey are attached comprise a C₄ -C₇ carbocyclic ring; and W represents##STR67## wherein each X is independently Cl or F; comprising heating amixture of a compound of the formula ##STR68## wherein R is C₆ H₅ CH₂,H, CH₃ or W and R³ is phenyl, with:(a) a hydrazine derivative of theformula R¹ R² CH--NH--NH--Z, wherein R¹ and R² are as defined above,provided that Y is --OR⁴, and Z is --CHO; or (b) a hydrazine derivativeof the formula R¹ R² CH--NH--NH--Z, wherein R¹ and R² are as definedabove, provided that Y is --OR⁴, and Z is --C(O)OC(CH₃)₃ or --C(O)OCH₂C₆ H₅, followed by hydrolyzing the Z group, and heating with atrialkylorthoformate and formic acid, in the optional presence of base,to form a triazolone of the formula ##STR69## wherein R, R¹ and R² areas defined above provided that Y is --OR⁴, and:i) where Y is present,for preparing a compound where Y is --OH, deprotecting to form atriazolone of the formula ##STR70## wherein R, R¹ and R² are as defined,and Y is --OH; or (ii) for forming a triazolone where R is H, treating atriazolone where R is C₆ H₅ CH₂ or CH₃ with HBr to form a triazolone ofthe formula ##STR71## wherein R¹ and R² are as defined above.
 4. Theprocess of claim 3 wherein a base is present in the mixture.
 5. Theprocess of claim 4 wherein the base is selected from a tertiary aminebase, hydroxide base, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo [2.2.2]octane, amoderate base and phosphazene base.
 6. The process of claim 5 whereinthe base is triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, K₂ CO₃ orphosphazene base.
 7. The process of claim 3 for preparing a triazolonewherein R is W, and R¹ and R² are independently C₁ -C₆ alkyl orY-substituted C₁ -C₆ alkyl, wherein Y is --OH or --OR⁴, and R⁴ is abenzyl group.
 8. The process of claim 7 wherein one of R¹ or R² is ethyland the other is Y-substituted ethyl.
 9. The process of claim 8 whereinthe triazolone has the formula ##STR72## wherein; Y is --OH or --OR⁴,wherein R⁴ is hydroxyl protecting group, andW represents ##STR73##wherein each X is independently Cl or F.
 10. The process of claim 9wherein a base is present in the mixture.
 11. The process of claim 10wherein the base is selected from a tertiary amine base, hydroxide base,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,1,4-diazabicyclo[2.2.2]octane, a moderate base and phosphazene base. 12.The process of claim 11 wherein the base is triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, K₂ CO₃ or phosphazene base.
 13. Theprocess of claim 7 wherein the deprotection in step (i) comprises: (a)treating with a solution of 40% to 50% HBr in water at a temperature of-10° C. to 40° C.; or (b) treating with a palladium hydrogenationcatalyst and formic acid.
 14. The process of claim 13 wherein thesolution is about 48% HBr and the temperature is 15° C. to 30° C. 15.The process of claim 3 wherein the hydrazine derivative of the formulaR¹ R² CH--NH--NH--Z is prepared by a process comprising the steps:(a)reacting a ketone of the formula R¹ --C(O)--R², wherein R¹ and R² are asdefined in claim 3, with a hydrazine of the formula H₂ N--NH--Z, whereinZ is as defined in claim 3, at a temperature of 0° to 80° C., to form acompound of the formula ##STR74## wherein R¹, R² and Z are as defined inclaim 3; and (b) reducing the product of step (a) by treating with ahydride reducing agent in a suitable solvent.
 16. The process of claim15 wherein the hydride reducing agent is sodium borohydride and thesolvent is a C₁ -C₄ alcohol.
 17. The process of claim 1 wherein B is agroup of the formula ##STR75## R is a group of the formula ##STR76##wherein X, E and G are as defined in claim 1, wherein the compound offormula ##STR77## wherein B and D are as defined in claim 1, is preparedby a process comprising the steps:(a) reacting a compound of the formula##STR78## wherein Q is a leaving group and E, X and G are as defined inclaim 1, in the presence of a base with the amino alcohol of the formula##STR79## to form a compound of the formula ##STR80## wherein R is asdefined above; and (b) treating the product of step (a) with a compoundof the formula ##STR81## wherein L is a leaving group and D is asdefined in claim 1 to form a compound of the formula ##STR82## wherein Band D are as defined in claim
 1. 18. The process of claim 3 wherein R isW and the compound of formula ##STR83## wherein R and R³ are as definedin claim 3, is prepared by a process comprising the steps:(a) reacting acompound of the formula ##STR84## wherein Q is a leaving group and X isas defined in claim 3, in the presence of a base with the amino alcoholof formula ##STR85## to form a compound of the formula ##STR86## whereinR is as defined in claim 3; and (b) treating the product of step (a)with a compound of the formula ##STR87## wherein L is a leaving groupselected from Cl, Br or I, and R³ is as defined in claim 3, to form acompound of the formula ##STR88##
 19. The process of claim 18 wherein Qis --OS(O)₂ R⁵ wherein R⁵ is C₁ -C₄ alkyl, CF₃, aryl, substituted arylor aryl(C₁ -C₄ alkyl); wherein"aryl" means a carbocylic aromatic group;and "substituted aryl" means an aryl group bearing one to threesubstituents selected from the group consisting of halo, alkyl, and C₁-C₆ alkoxy.